The purpose of this study is to document genotypic differences and biotin-responsiveness in family pedigrees with pyruvate carboxylase deficiency. Brainstem and diffuse subcortical white matter changes are found on MRI in several members of this kindred. Improvement in myelination is found on serial MRI after one child received biotin therapy. The pathophysiologic basis underlying these myelin changes may involve PC's role in providing citrate and cytosolic acetyl Co-A as sources for fatty acid synthesis. It is not clear whether the improved myelination in this patient is a consequence of early biotin treatment or simply reflects the natural course of this disease. His parents' fibroblast PC enzyme activity (55~65% of the mean of controls) was consistent with that predicted for obligate heterozygotes. There was a small increase in PC activity in the parent's lymphocyte PC activity. The genetic sequence of the biotin binding domains in all family members appear normal. Studies are in progress to define the mutations in the PC gene responsible for this disorder.